JPH06179673A - New piperazine and homopiperazine derivative, medicinal composition containing these compound and production of these compound - Google Patents

Abstract

PURPOSE:To obtain a new piperazine compound useful as a medicine for preventing lipid peroxidation. CONSTITUTION:The compound of formula I [Lip is H, 15-20C alkyl, 10-20C alkanoyl, 10-20C alkenoyl, (halogen substituted) trityl, adamantyl, 1- or 2- naphthyloxy, oxo-substituted tetrahydronaphthyloxy or amine protecting group; A1 and A2 are (substituted)2-3C alkylene; n is l-2; Het is a group expressed by formula II (R1 is amino or 1-pyrrolidinyl), etc., with proviso that when Het exhibits the formula II and A1 and A2 are single bonds, Lip is not H], e.g. 1-(10-undecenoyl)-4-[2,6-di(1-pyrrolidinyl)-4-pyrimidinyl]piperazine. The compound of formula I is obtained by reacting a compound of the formula Lip-A1-L1 (L1 is removable group) with a compound of formula III.

Description

Detailed Description of the Invention

The present invention relates to novel piperazine and homopiperazine derivatives having lipid peroxidation inhibitory activity, pharmaceutical compositions containing these compounds and a method for producing these compounds.

[0002] In vivo lipid peroxidation is known to be a metal ion-catalyzed radical process that plays an important role in many pathological diseases and illnesses and aging. Such diseases and disorders associated with lipid peroxidation include tissue damage resulting from, for example, brain and spinal cord injury, stroke, certain types of cerebrovascular spasm, ischemia (particularly during and after so-called restoration of blood flow). Reperfusion injury), in addition, myocardial infarction, atherosclerosis,
Inflammatory diseases such as rheumatoid arthritis, various autoimmune diseases,
Drug toxicity, asthma, etc. [eg B. Halliwell,
FASEB J. 1 , 358 (1987) and JM Gutteridge and
B. Halliwell, Methods in Enzymology 186 , 1 (1990)
reference〕.

On the one hand, intensive research is carried out worldwide in order to find substances (antioxidants) which generally block oxidative processes in vivo and, on the other hand, to find active substances which especially block the peroxidation of lipids. Is done in a regular manner. Compounds exhibiting the latter type of activity may be used in mammals, including humans, to prevent and / or treat diseases and disorders such as those mentioned above associated with lipid peroxidation processes. it can. Such agents have significant therapeutic importance, and compounds of potential use as pharmaceuticals, which may be used, for example, in the treatment of central nervous system injuries.

Some endogenous substances that block lipid peroxidation are present in the mammalian internal regulatory system. One of these substances is α-tocopherol, or vitamin E.
[For example, MJC Kelly, “Progress in Medi
cinal Chemistry "Vol. 25, p. 250, ed .: GP Ellis
And GB West, Elsevier Science Publishers, 198
8].

The object of the present invention is itself useful for treating various diseases and disorders in mammals, including humans, which can effectively inhibit lipid peroxidation and in which inhibition of lipid peroxidation is desired. The aim is to develop certain novel piperazine and homopiperazine derivatives.

Surprisingly, this requirement is a 6-membered nitrogen heterocycle, for example a substituted pyrimidine or a similar fused heterocycle such as phenylpteridine, which heterocycle is piperazine (or homopiperazine). ) Having it attached to one of the nitrogen atoms, either directly or through a lower alkylene chain, and at the same time a hydrocarbyl group (or optionally hydrogen), such as the hydrocarbyls exemplified below, is piperazine (or homo-). It was found to be significantly satisfied by certain piperazine and homopiperazine derivatives linked to other nitrogens of the piperazine) ring. Numerous compounds consisting of these three types of structural units, namely open or cyclic hydrocarbyl groups, piperazine rings and substituted nitrogen heterocycles, have been described in the literature.

Such compounds exhibit various biological actions. One of these important compounds includes molecules in which the above-mentioned nitrogen heterocycle is, for example, a pyridine or pyrimidine ring substituted by an amino group, and the hydrocarbyl group is extensively modified. That is, the hydrocarbyl group is, for example, a steroid skeleton (P
CT-Application No. WO 87/01706 and WO 87/07895), Seco-steroids (published PCT-Application No. WO 88/0752).
7) Alternatively, various substituted alkyl groups of medium chain length, various monocyclic and bicyclic groups, such as substituted phenyl, phenoxyalkyl, benzopyranyl and the like (published PCT-application WO 88 / 08424) can be. These compounds are described as having lipid peroxidation inhibiting activity. However, it should be noted that such molecules with alkenyl, alkanoyl, alkenoyl or alkyl of more than 14 carbon atoms have not been disclosed.

In another group of compounds containing the three unique structural elements mentioned above, in addition to the nitrogen heterocycles whose nitrogen heterocycles are almost identical to those described in the above section, the abovementioned hydrocarbyl groups are also mentioned. There are various types of hydrocarbyl groups similar or different from. Thus, for example, phenyl, benzyl and benzhydryl [France patent specification No. 1,507,062, published German patent applications No. 1,947,332 and 2,211,738, Belgian patent specification
No. 739,283 and JP-A-49-76887], benzodioxolyl and benzodioxanyl [Canadian patent specification
No. 979,894 and JP-A-49-72270, JP-A-49-72271
, JP-A-49-72272 and JP-A-49-72273], and 3-trityl-n-propyl group [GL Regnier et al.
J. Med. Chem. 15 , 295 (1972)] exists as a unique structural element. (The fact that derivatives containing naphthyloxyalkyl, trityl or adamantyl linked to the piperazine nitrogen are not mentioned in the above compounds means that
I have to pay attention.) It has been described that a number of the latter compounds exhibit various biological actions (for example, vasodilatory action, sedative action, analgesic action, anti-inflammatory action and respiratory promoting action), but lipid peroxidation inhibitory activity is Not listed at all.

A piperazine ring and, in addition,
In addition to the above compounds containing a nitrogen heterocycle, several other types of compounds have been announced to block lipid peroxidation. Some examples are as follows. Cyclic hydroxamic acid (Y. Teshima et al., J. Antibiot. 44 , 685 (199
1)]; Pyrimidinedione [published European patent application No.
447,324]; Acylamino-7-hydroxyindane derivatives [Y. Oshiro et al., J. Med. Chem. 34 , 2014 (199
1)]; amino homologue of vitamin C [published European patent application Nos. 446,539 and 447,325]; monocyclic homologue of vitamin E [JP-A 1-226843]; 4-arylthiopiperidine derivative [published European Patent Application No. 433,167];
1,4-benzoquinone [for example, G. Goto, Chem. Pharm.
Bull. 33 , 4422 (1985)]; carboxyalkyl and hydroxyalkyl naphthoquinones [K. Okamoto et al., Che
m. Pharm. Bull. 30 , 2797 (1982)]; selenium compounds [A. Muller et al., Biochem. Pharmacol. 33, 3235 (198).
4) and AL Tappel, Fed. Proc. 24 , 73 (1965)];
Curcuminoids [S. Toda et al., J. Ethnopharmacology 2
3 , 105 (1988)]; quinazoline derivative [published European patent application No. 302,967]; pyridylquinoline [published European patent application No. 289,365]; dihydroquinoline derivative [A. Blazovics et al., Free Radical Res. Commun . 4, 409
(1988)]; Anthrone and acridine derivatives [P. Fr.
ank, Biochem. Biophys. Res. Commun. 140 , 797 (198
6)]; Dihydropyridinethione [AG Odynets et al., Eks
p. Med. (Riga) 21 , 127 (1986); Chem. Abstr. 106 ,
148956]; Pyrazolone derivative [JP-A-62-149617];
Benzothiazine [JP-A 1-287077]; flavonoids [see, for example, R. Campos et al., Planta Med. 55 , 417 (1989)]; pyrimidopyrimidine [I. Bellido et al., Meth. Fin
d. Exp. Clin. Pharmacol. 13 , 371 (1991)]; methylated uric acid analog [Y. Nishida, J. Pharm. Pharmacol. 43 ,
885 (1991)]; Methylprednisolone [eg HB
Demopoulos et al., Can. J. Physiol. Pharmacol. 60 , 1415
(1982)]; Dehydroalanine derivative [P. Buc-Cal
deron et al., Arch. Biochem. Biophys. 273 , 339 (198
9)]; Acylated polyamines [JM Braughler et al., Bioch
em. Pharmacol. 37 , 3853 (1988)].

The above mentioned literature data indicate that compounds containing mono- or diamino-substituted nitrogen heterocycles attached to the piperazine ring do not necessarily prevent lipid peroxidation and, on the other hand, the presence of said nitrogen heterocycle is the same. It shows that it is not absolutely necessary for biological activity.

As mentioned above, the desired lipid peroxidation inhibiting activity is also exhibited by certain novel piperazine derivatives in which the phenylpteridine ring system is optionally linked via the alkylene chain to one of the nitrogens in the piperazine ring. .
In the most preferred compounds of this type, no other nitrogen is substituted.

Belgian patent specification No. 901,850 and published German patent application No. 2,700,073 have the general formula (A)

[Chemical 33] Where R represents a substituted amino and Alk
(Meaning an optionally substituted alkylene chain). In these compounds, R is, for example, mono- or dialkylamino,
Benzylamino or a 5 or 6 membered heterocyclic group optionally containing 1 or 2 additional heteroatoms,
It can be, for example, morpholinyl, piperidinyl, pyrrolidinyl or 4-methyl-1-piperazinyl.
These patent specifications do not describe compounds containing a piperazinyl group which is unsubstituted or substituted in the 4-position by groups other than methyl as R. The above two patent specifications and documents [eg H. Priewer
Et al, Arzneim.-Forsch./Drug Res. 35 , 1819 (1985); P.
harm. Res. 3 , 102 (1986); Drugs of the Future 11 ,
669 (1986)], the above compound has diuretic activity,
Although it is described that it has potassium-retaining activity, calcium antagonist activity and cardioprotective activity, it does not describe lipid peroxidation inhibitory activity.

In the novel lipid peroxidation-inhibiting novel piperazine and homopiperazine derivatives, a 6-membered optionally containing two nitrogen atoms and optionally fused with a benzene or pyrazine ring Is an optionally substituted heterocycle (eg, pyrimidine, pyridazine, quinazoline or pteridine) attached to one of the nitrogen atoms in the piperazine (or homopiperazine) ring, optionally via an alkylene chain. And at the same time, a long-chain open-chain hydrocarbyl group,
A moiety containing two optionally partially saturated fused carbocycles (eg naphthyl) linked through an oxygen atom and a lower alkylene chain, a methyl group having three unfused unsaturated carbocycles (eg trityl). ) Or a moiety consisting of three fused saturated carbocycles (eg adamantyl) can be attached to another nitrogen atom of the piperazine (or homopiperazine) ring. Alternatively, the latter nitrogen may also be unsubstituted.

Accordingly, the present invention is directed to the general formula (I)

[Chemical 34] And a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical composition containing these compounds.

[0015] In the above formula, Lip is hydrogen; C ₁₅ ~
C ₂₀ alkyl; C ₁₀ -C ₂₀ alkanoyl or C ₁₀ -C
₂₀ alkenoyl; trityl optionally substituted by halogen; adamantyl; 1- or 2
A naphthyloxy or oxo substituted tetrahydronaphthyloxy; or an amine protecting group commonly used eg in peptide chemistry, wherein A ¹ and A ² are independently substituted by a single bond and optionally hydroxy or oxo Optionally selected from the group consisting of C ₂ -C ₃ alkylene, n is 1 or 2 and Het is of the general formula (a)

[Chemical 35] (Wherein R ¹ is amino or 1-pyrrolidinyl)
Or a group of formula (b)

[Chemical 36] 4-chloro-3-oxo-2,3-dihydro-5-pyridazinyl group, or

Formula (c)

[Chemical 37] 4-amino-6,7-dimethoxy-2-quinazolinyl group of formula (d)

[Chemical 38] 4,7-diamino-6-phenyl-2-pteridinyl group of, or the formula (e)

[Chemical Formula 39] 2,7-diamino-6-phenyl-4-pteridinyl group, or

Formula (f)

[Chemical 40] 2,4,7-triamino-6-pteridinylcarbonyl group of, or the general formula (g)

[Chemical 41] Where X represents oxygen, sulfur or nitrogen optionally substituted by lower alkyl, and with the proviso that

First, when Het represents a group of general formula (a) and A ¹ and A ² both represent a single bond,
Lip is not hydrogen and, secondly, when Lip is different from naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ means a single bond and thirdly,
When Lip represents naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ is not a single bond,
And, fourth, A ¹ and A ² cannot simultaneously represent C ₂ -C ₃ alkylene optionally substituted by hydroxy or oxo.

According to another aspect of the present invention, the general formula (I)
And a method for producing a pharmaceutically acceptable salt thereof. Due to the lipid peroxidation inhibitory effect of the compound,
Preferred compounds are, Lip is means open-chain or cyclic lipophilic group, e.g. C ₁₀ -C ₂₀ alkenoyl, o- chlorotrityl, 1- or 2-naphthyloxy, A
¹ represents a single bond, 2-hydroxy-1,3-propylene or CH ₂ CO, A ² represents a single bond, and n represents
1 or 2 and Het is a compound of general formula (I) meaning a group of general formula (a). Similarly, due to the lipid peroxidation inhibiting effect of the compound, the preferred compound is Li
p means hydrogen, A ¹ is a single bond, and A ² is
1,3-propylene optionally substituted by hydroxy or ethylene optionally substituted by oxo, n is 1 or 2 and Het is of the general formula (g) Are compounds of general formula (I), in which the groups of formula (X are as described above) are represented.

Certain compounds of general formula (I), where Lip represents an amine protecting group commonly used in peptide chemistry, are useful intermediates in the synthesis of other compounds of general formula (I). , Is advantageous.

The pharmaceutically acceptable acid addition salts of the compounds of general formula (I) are formed using the usual known non-toxic organic or inorganic acids. Such salts include hydrochlorides, sulfates, phosphates, tartrates, fumarates, citrates and the like.

The compounds of the present invention can be prepared using various methods known per se. These methods are based on the individual structural elements of the compounds of the invention, namely Li
p, piperazine (or homopiperazine) ring and He
They differ from each other in the order of coupling of t.
According to the invention, the general formula (I)

[Chemical 42] The compound (wherein Lip, A ¹ , n, A ² and Het are as described above) and a pharmaceutically acceptable acid addition salt thereof can be produced by the following method.

(A) General formula (I) [wherein Lip is
Provided that it is not a hydrogen or amine protecting group, as defined in the description of the compound above and A ¹ is not a single bond if Lip represents naphthyloxy or oxo substituted tetrahydronaphthyloxy. And n, A ² and Het are as defined in the description of the compound above, to prepare a compound of general formula (II) Lip-A ^1- L ¹ (II) where Lip and A ¹ are as described above and L ¹
Is a scavenging group)

[Chemical 43] (Where n, A ² and Het are as described above), or

(B) General formula (I) [wherein Lip means naphthyloxy or oxo-substituted tetrahydronaphthyloxy, and A ¹ is 1,3 substituted by hydroxy]
-Indicating propylene and n, A ² and Het are as defined in the description of the compounds above) to prepare a compound of general formula (IV)

[Chemical 44] (Wherein Lip is as described above) is represented by the general formula (III)

[Chemical formula 45] (Where n, A ² and Het are as described above).
Of the compound, or

(C) General formula (I) [wherein Lip is
As defined in the description of the compound above, provided that it is not hydrogen, A ¹ is provided that A ¹ is not a single bond when Lip represents naphthyloxy or oxo-substituted tetrahydronaphthyloxy. And Lip is as defined in the description of the compound above, with the proviso that A ¹ is a single bond when Lip represents an amine protecting group, and n, A ² and Het are defined in the description of the compound above. To produce a compound of general formula (V)

[Chemical formula 46] (Wherein, Lip, A ¹ and n are as described above) with a compound of general formula ^{(VI) L 2 -A 2 -Het} (VI) ( wherein, A ² and Het are as described above and L ² represents a removing group), or

(D) General formula (I) [Lip means naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ is defined in the above description of the compound, provided that it is not a single bond. And n, A ² and Het are as defined for formula (I)] to prepare compounds of general formula (VI
I)

[Chemical 47] (Wherein A ¹ , n, A ² and Het are as described above and L ¹ represents a leaving group) and a compound of the general formula Lip-
H with a compound of H, where Lip is as described above, or

(E) General formula (I) [wherein Lip is
As defined in the above description of compounds, provided that it is not naphthyloxy or oxo substituted tetrahydronaphthyloxy, A ¹ is a single bond,
Het is the general formula (g)

[Chemical 48] To prepare a compound of formula (VIII), wherein X is as defined in the description of the compound above and n and A ² are as defined above.

[Chemical 49] Where Lip is as described above, provided that it is not hydrogen, naphthyloxy or oxo substituted tetrahydronaphthyloxy, and X is optionally substituted by oxygen, sulfur or lower alkyl. Means nitrogen and n and A ² are as described above)
The compound of formula (IX)

[Chemical 50] Is reacted with 5-nitroso-2,4,6-triaminopyrimidine and if Lip represents an amine protecting group, this protecting group is removed from the compound thus obtained,
Or

(F) General formula (I) [Lip is as defined in the above description of the compound, provided that it is not naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ and A ² are both , A single bond, and Het has the formula (d)

[Chemical 51] And n is as defined above in the description of compounds] to prepare a compound of general formula (X)

[Chemical 52] Where Lip is as described above and n is as described above, provided that it is not hydrogen, naphthyloxy or oxo substituted tetrahydronaphthyloxy), and If Lip represents an amine protecting group, this protecting group is removed from the product thus obtained, or

(G) General formula (I) [wherein Lip is as defined in the description of the above compounds, provided that it is not naphthyloxy or oxo substituted tetrahydronaphthyloxy, A ¹ and A ² is both a single bond and Het has the formula (e)

[Chemical 53] And n is as defined above in the description of compounds] to prepare a compound of the general formula (X
I)

[Chemical 54] Where Lip is as described above and n is as described above, provided that it is not hydrogen, naphthyloxy or oxo-substituted tetrahydronaphthyloxy, and then is reacted with benzyl cyanide and Li
if p represents an amine protecting group, this protecting group is removed from the resulting product, or

(H) General formula (I) [Lip is as defined in the description of the above compounds, provided that it is not naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ and A ² are Both are single bonds and Het has the formula (f)

[Chemical 55] Embedded image and n is as defined for formula (I) to prepare a compound of formula (XII)

[Chemical 56] Where Lip is as described above and n is as described above, provided that it is not hydrogen, naphthyloxy or oxo substituted tetrahydronaphthyloxy, and a compound of formula (IX)

[Chemical 57] Was reacted with 5-nitroso-2,4,6-triaminopyrimidine and if Lip represents an amine protecting group, this protecting group was removed from the product thus obtained and, if necessary, Accordingly, the compound of general formula (I) produced by any of the above methods (a) to (h) is converted into its acid addition salt.

The leaving groups L ¹ and L ² in the compounds of the general formulas (II), (VI) and (VII) are independently a halogen atom such as chlorine, bromine or iodine, or a sulfonyloxy group such as It is methanesulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy.

The amine protecting group as Lip in the compounds of general formula (V), (VIII), (X), (XI) or (XII) can be any group of this type commonly used in peptide chemistry. Is. Preferred protecting groups are, for example, tert-butoxycarbonyl, formyl, benzyloxycarbonyl and the like.

Preferred embodiments of the above methods (a) to (h) will be described in detail below. Process (a) optionally at a temperature between 0 ° C. and the reflux temperature of the solvent in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine or pyridine, an inert organic solvent such as chloroform or methylene chloride. A compound of general formula (II) in a halogenated hydrocarbon such as, an alcohol such as methanol or ethanol, an ether-like solvent such as diethyl ether or tetrahydrofuran, acetonitrile, dimethylformamide, etc. React with. Pyridine can also be used as a solvent. The compounds of general formula (II) used as starting materials are either commercially available or can be prepared by methods known from the literature.

In the preparation of the compound of the general formula (I), wherein Lip means alkanoyl or alkenoyl and A ¹ is a single bond, the above-mentioned acyl group is a compound in which L ¹ is hydroxy. It can also be introduced by using a carboxylic acid of the general formula (II) In such cases, the reaction with the compound of general formula (III) is
It is preferably carried out in the presence of a condensing agent such as carbonyldiimidazole or a carbodiimide, eg dicyclohexylcarbodiimide and the like. General formula (II
Certain compounds of I) are described in the literature [eg published PCT patent application No. WO 87/01706; TH Althuis and HJ He.
ss: J. Med. Chem, 20 , 146 (1977)]. Other related compounds can be made by using the methods illustrated by the examples below.

Method (b) A compound of general formula (IV) is treated with a compound of general formula (III) in an inert solvent such as an alcohol, eg methanol or ethanol, at a temperature between room temperature and the reflux temperature of the solvent. React. The starting materials of general formula (IV) are known from literature or similar methods [E. Fourneau and M. Tr.
efouel, Bull. Soc. Chim. France 〔4〕, 43 , 454 (19
28)].

Method (c) A compound of general formula (V) of general formula (VI) at a temperature between 50 ° C. and 200 ° C. and under conditions similar to those described for method (b) above. React with compounds. The starting materials of general formulas (V) and (VI) are known or can be prepared analogously to known compounds [eg PE Aldri
ch et al., J. Med. Chem. 14 , 535 (1971); B. Roth et al., J.
Am. Chem. Soc. 72 , 1914 (1950); J. Mowry, J. Am.Ch
em. Soc. 75 , 1909 (1953); published German patent application
No. 2,550,111 and published PCT patent application No. WO
87/01706 and WO 88/08424].

Process (d) A polar solvent such as acetonitrile or dimethylformamide at a temperature between 0 ° C. and the boiling point of the solvent, optionally in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine or pyridine. , Halogenated hydrocarbons, for example chloroform or methylene chloride, in an inert organic solvent of the general formula (VI
The compound of I) is reacted with a compound of general formula Lip-H. Alternatively, a salt of general formula Lip-H (eg an alkali metal salt) can be formed with a suitable base and reacted with a compound of general formula (VII). The starting materials of the general formula (VII) under conditions described for the method (a), general formula L ¹ -A ¹ -L ² wherein a suitable compound of general formula (III), A ¹ Is as defined for general formula (I) in the description of compounds and provided that it is not a single bond and L ¹ and L ²
Can independently be produced by reacting with a compound of

Method (e) Alkali metal hydroxide, carbonate or alkoxide,
A substituted alcohol in the presence of a strong base such as sodium hydroxide, potassium carbonate or sodium 2-ethoxyethoxide at a temperature between room temperature and the reflux temperature of the solvent, preferably 100 ° C to 140 ° C. 2,4,7-triamino-6-in an inert solvent such as 2-methoxyethanol or 2-ethoxyethanol, dimethylformamide, N-methylpyrrolidone and the like.
For the preparation of arylpteridines, reference [eg D.
J. Brown: “Fused Pyrimidines”, 113-120 and 359 ~
Page 360, Series “The Chemistry of Heterocyclic Comp
ounds ", Eds. EC Taylor and A. Weissberger“, J
Ohn Wiley and Sons, Interscience (1988); Hungarian Patent Specification No. 195,817] under normal conditions.
React with nitroso-2,4,6-triaminopyrimidine. If in process (e) a compound of general formula (I) containing an amine protecting group as Lip is prepared, this protecting group is removed by customary methods known per se, for example in separate reaction steps. be able to. The method used to remove the protecting group is selected by the nature of the protecting group in question. Thus, for example, tert-butoxycarbonyl can be removed in an aqueous or anhydrous medium using a suitable acid such as hydrochloric acid, formic acid or trifluoroacetic acid; and benzyloxycarbonyl can be removed, for example by catalytic hydrogenation. Although capable of being cleaved, formyl can be removed by using a strong mineral acid such as hydrochloric acid or a strong base such as an alkali metal hydroxide under heat. Alternatively to this, the general formula (I) containing an amine protecting group as Lip
The compound of 1 can be further reacted without isolation. That is, the protecting group can be removed in the same reaction mixture used for the preparation of the protected compound. In this case, the unprotected final compound of formula (I) where Lip is hydrogen is isolated and purified.

The starting compound of general formula (VIII) can be prepared, for example, by either of the two methods shown by the following reaction schemes.

[0040]

[Chemical 58]

According to Method A shown in the reaction scheme,
First, the general formula (Va) [wherein Lip and n are
A compound of the general formula (I) as defined in the description of general formula (I), that is, a compound of general formula (V) in which A ¹ is a single bond, with the proviso that Lip is not hydrogen.
For example, under the conditions described for method (a) above, the general formula L ¹ -A ² -L ² [wherein A ² is of the general formula (I) provided that it is not a single bond. Of the general formula (XIII) or (XIV) [wherein L ¹ and L ² are independently scavenging groups] or epichlorohydrin [wherein Lip, n and R ² are as defined in the description of general formula (I), with the proviso that A ² is not a single bond and L ²
Means a removing group].

Then, the compound of the general formula (XIII) or (XIV) thus obtained is treated with a compound of the general formula (XV) in an inert organic solvent, optionally in the presence of a base.
Reacting with a substituted benzyl cyanide of the formula wherein X is oxygen, sulfur or nitrogen optionally substituted by lower alkyl to give the desired intermediate of general formula (VIII) .

Instead of this, according to method (B) shown in the scheme, firstly in a manner known per se, under the conditions described for method (A) above, the general formula (XV ) [Wherein X is as described above] substituted benzyl cyanide is represented by the general formula L ¹ -A ² -L ² [wherein
L ¹ , L ² and A ² are as described above] or epichlorohydrin. Then, the compound of the general formula (XVI) or (XVII) thus obtained is reacted with the compound of the general formula (Va) [wherein Lip and n are as described above] to give a compound of the general formula (Va). VII
Obtain the desired intermediate of I).

The starting materials used in the above two methods, ie the compounds of the general formulas (Va) and (XV), are known or are prepared using known methods described below in the examples. be able to. The compounds of the general formula L ¹ -A ² -L ² are likewise known. Preferred compounds of this type are, for example, 1-bromo-3-chloropropane and 2-chloroacetyl chloride.

The 5-nitroso-2,4,6-triaminopyrimidines of formula (IX) used as starting materials in the process of the invention are also known [eg H. Sato et al., J.
Chem. Soc. Japan. Pure Chem. Sect. 72 , 866 (1951)
reference〕.

Method (f) A compound of the general formula (X) can be reacted with benzyl cyanide, for example using the method described in method (e), and optionally a protecting group which may be present. Can be removed, for example, in the same manner as described herein.

The starting compound of the general formula (X) can be obtained, for example, by first describing the general formula (Va)

[Chemical 59] [Wherein Lip and n are as defined in the description of general formula (I), provided that Lip is not hydrogen, for example, published European Patent Application No.
By reacting with S-methylisothiuronium iodide in the manner described in 0,039,190

[Chemical 60] [Wherein Lip and n are as defined in formula (Va)] can be prepared by a method for obtaining a piperazinyl amidine hydroiodide.

Next, for example, EC Taylor et al. [J. Am. Che
m. Soc. 81 , 2442 (1959)] by reaction with isonitron malonitrile from a compound of general formula (XVIII) to a general formula (XIX)

[Chemical formula 61] Where Lip and n are as defined in formula (Va). Finally, the salt of the general formula (XIX) thus obtained is isomerized by heating with a suitable base such as an alkali metal hydroxide or an alkali metal carbonate. Obtain the desired intermediate of (X).

The final step for preparing the compound of general formula (X) (isomerization) and the subsequent reaction with benzyl cyanide to give the compound of general formula (I) is described, for example, in Hungarian patent specification No. 195,815. It should be noted that in the manner described, the compound of general formula (X) can be conveniently carried out in the same reaction mixture without isolation.

Method (g) A compound of the general formula (XI) can be reacted with benzyl cyanide under the conditions described for method (e) and the protecting group finally present is likewise For example, it can be removed by the method described in the specification.

The starting material of the general formula (XI) can be obtained by using the method described in the above-cited reference by H. Sato et al. (See the explanation of the method (e)).

[Chemical formula 62] [Wherein Lip and n are as defined in the explanation of the general formula (I), provided that Lip is not hydrogen], and can be produced by a method of treating with nitrous acid. .

General formula (XX) used as starting material
In a manner known per se [UK patent specification N
No. 2,198,132], 4-chloro-2,6-diaminopyrimidine and the appropriate compound of the general formula (Va).

Process (h) A compound of the general formula (XII) can be prepared, for example, under the conditions described for process (e), 5-nitroso-2,4,6 of the formula (IX).
-The triaminopyrimidine can be reacted and the finally present protecting group can be removed in analogy to the methods described herein.

The starting material of formula (XII) can be prepared by known methods [eg TS Osdene et al., J. Med. Chem. 10 , 165 (1
967)], ethyl cyanoacetate and the general formula (Va)

[Chemical formula 63] Embedded image wherein Lip and n are as defined in the description of the compound of general formula (X).

Acid addition salts of compounds of general formula (I) can be prepared by using any of the general methods known per se, for example in inert organic solvents, water or mixtures thereof. Of the base with 1 to 4 equivalents of the desired acid and the salt obtained therefrom in a known manner (eg filtration, evaporation of solvent, trituration with solvent and / or)
It can be produced by isolation by precipitation with a non-solvent).

When the protecting group is removed from a compound of general formula (I) containing an amine protecting group as Lip by using an acid, a general formula containing hydrogen as Lip is used.
The corresponding acid addition salts of the compounds of (I) can be obtained directly.

The compounds of the general formula (I) according to the invention and their pharmaceutically acceptable acid addition salts exhibit valuable biological activity. More specifically, these compounds are
It is useful in the treatment and / or prevention of diseases and disorders in which the inhibition of lipid peroxidation and therefore inhibition of lipid peroxidation is desired.

Specific examples of the above-mentioned diseases include ischemia and disorders associated with recanalization of blood such as digestive ulcers such as stress ulcers, cardiac ischemic diseases such as myocardial infarction and arrhythmia, and cerebral hemorrhage
Caused by cerebrovascular disease such as cerebral infarction / transient cerebral ischemic attack, liver and renal damage due to transplantation / microcirculatory failure, or lipid peroxidation due to active oxygen abnormally generated due to causes other than ischemia Various possible cell disorders, such as Behcet's disease, cutaneous vasculitis, ulcerative colitis, malignant rheumatism, arthritis, arteriosclerosis,
Diabetes etc.

The lipid peroxidation inhibitory activity of the compounds of the invention and their pharmaceutically acceptable salts is demonstrated and measured by biochemical and pharmacological studies. Listed below are some tests for the compounds of the invention and the results obtained in these tests.

In these studies, known lipid peroxidation inhibitors such as 3,5-di (tertiary butyl) -4-hydroxytoluene ["butylated hydroxytoluene", BH
T, eg W. Snipes et al., Science 188 , 64 (1975)], α-tocopherol [vitamin E, eg MJ Kelly references cited above], 21- [4- [2,
6-di (1-pyrrolidinyl) -4-pyrimidinyl] -1
-Piperazinyl] -16α-methyl-pregna-1,4,
9 (11) -triene-3,20-dione [U74006F, eg JM Braughler et al., J. Biol. Chem. 262 , 10438.
(1987)] and 2-[[4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -1-piperazinyl] methyl] -6-hydroxy-2,5,7,8-tetramethyl -3,4-dihydro-2H-1-benzopyran [U
78517F, eg ED Hall et al., J. Pharmacol. Exp. The
r. 258 , 688 (1991)] was used as the reference compound.

Biochemical investigation 1. JM Braughler et al. (J. Biol. Chem. 262 , 10438
(1987)] and JA Buege and SD Aust [Methods
In Enzymology 52 , 302 (1978)], ferrous ion-dependent lipid peroxidation inhibitory activity was measured on rat brain homogenates. The IC ₅₀ values (in micromolar) of some compounds of the invention measured in this test and of the reference compounds
IC ₅₀ values are as summarized in Table 1 below. The IC ₅₀ value is defined as the concentration of test substance that reduces by 50% the amount of thiobarbituric acid-reactive substances (primarily malondialdehyde) considered to be a unique parameter of lipid peroxidation.

[0062]

[Table 1]

2. In addition, JM Braughler et al. [J. Bio
l. Chem. 262 , 10438 (1987)] and JA Buege and S. D, Aust (Methods in Enzymology 52 , 302 (197).
The inhibition of ferrous ion-dependent peroxidation of arachidonic acid was measured by the method of [8]]. The IC ₅₀ values (in micromoles) of some compounds of the invention and the IC _{50 of the} reference compound measured in this test are as shown in Table 2.

[0064]

[Table 2]

3. TJ Player and AA Horton
[J. Neurochem. 37 , 422 (1981)] and Z. Duniec [B.
iochem. Pharmacol. 32 , 2283 (1983)], NA
The inhibition of DPH-dependent lipid peroxidation was measured. The IC ₅₀ values of some compounds of the invention (in micromolar) and the IC ₅₀ values of reference compounds measured in this test are as shown in Table 3.

[0066]

[Table 3]

Pharmacological investigation 1. The compounds of the invention as well as the reference compound are ED Ha
ll et al. [J. Neurosurg. 68 , 456 (1988)] to prevent acute brain injury in mice. The dose of test compound administered by the intravenous method and the% improvement in neurological status are summarized in Table 4.

[0068]

[Table 4]

2. DA Parks et al. (Surgery 92 , 896
(1982)], the compounds of the invention prevent ischemia-induced weight gain of defined areas in the rat small intestine. Percentage of inhibition observed after administration of a 25 mg / kg oral dose of a compound of the invention or reference compound
Is as shown in Tables 5 and 6.

[0070]

[Table 5]

[0071]

[Table 6]

Toxicity The acute toxicity of certain compounds of the present invention was measured in rats and was found to be generally advantageously low. That is, for example, in Examples 1, 10, 27, 28,
An oral dose of 1000 mg / kg of compounds 34 and 50 did not induce mortality in any of the drug-treated animals, similar to the toxicity measured against the reference compound U74006F above (ie LD ₅₀ > 1000 mg). /kg).

The above data demonstrate that some compounds of general formula (I) of the present invention inhibit lipid peroxidation in in vitro tests. Thereby, these compounds are able to inhibit various pathological processes associated with an increased rate of lipid peroxidation in vivo, as evidenced by the above results in in vivo studies. Furthermore, this beneficial activity is associated with low toxicity.

For therapeutic purposes, the compounds of the invention and their pharmaceutically acceptable salts can be used alone or in the form of pharmaceutical compositions. Such compositions may be admixed with the known carriers, excipients, diluents and / or other additives commonly used in formulation, as the active ingredient, sufficient to provide the desired effect. It contains a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof in an amount.

The present invention also relates to methods of inhibiting lipid peroxidation and treating diseases and disorders in which inhibition of lipid peroxidation is desired. The method comprises administering to a patient in need of such treatment a therapeutically effective amount of an active ingredient of formula (I) or a pharmaceutically acceptable salt thereof.

The therapeutically effective dose of the compounds of this invention can vary, and will generally depend on the condition and age of the individual patient being treated, and ultimately determined by the physician, but Oral daily doses of between 0.1 mg and about 100 mg of these compounds per kg body weight can be used for the prophylaxis and / or treatment of diseases in which inhibition of lipid peroxidation is desired.

Further, the present invention will be described in more detail by the following examples, which, however, do not limit the present invention.

Example 1 1- (10-undecenoyl) -4- [2,6-di (1
-Pyrrolidinyl) -4-pyrimidinyl] piperazine 1- [2,6-di (1-
Pyrrolidinyl) -4-pyrimidinyl] piperazine (2.
To a solution of 25 g, 7.4 mmol) 10-undecenoyl chloride (1.85 ml, 1.75 g, 8.6 mmol) is added dropwise with stirring at 0-5 ° C. The reaction mixture is stirred at the same temperature for 1 hour and then 450 ml of water
Add to. After stirring for 15 minutes, a yellow powdery precipitate is collected, washed with water and dried. The crude product was recrystallized from acetonitrile to give 2.86 g of the title compound. Yield: 82.0%. Melting point 93-96 [deg.] C.

The starting material 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine is prepared, for example, as described in the literature [published PCT application WO 87/01706]. be able to. In a similar manner, 1- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] homopiperazine was prepared. Yield: 68.4
%. Melting point 106-110 [deg.] C.

Example 2 1- (n-octadecanoyl) -4- [2,6-di (1
-Pyrrolidinyl) -4-pyrimidinyl] piperazine 10-Undecenoyl chloride was replaced with n-octadecanoyl chloride by the procedure of the example except that the title compound was obtained in a yield of 50.0%. Obtained. Melting point 102-104 ° C.

Example 3 1- (10-Undecenoyl) -4- (2,6-diamino-4-pyrimidinyl) -piperazine 1- (2,6-Diamino-4-pyrimidinyl) piperazine- in acetonitrile (120 ml) A mixture of bis-trifluoroacetate (1.26 g, 3.0 mmol) and anhydrous potassium carbonate (1.38 g, 10.0 mmol) is stirred under reflux for 30 minutes. Then 10-undecenoyl chloride (0.74 ml, 0.70 g, 3.4
Mmol) and stirring under reflux is continued for 1 hour, after cooling the solvent is evaporated under reduced pressure and the residue is partitioned between methylene chloride (100 ml) and water (100 ml). The aqueous layer is separated and methylene chloride (40 each)
ml) twice. The combined organic extracts are washed twice with water (until neutral), dried over MgSO ₄ and then concentrated under reduced pressure. The crude product obtained is triturated with isopropyl ether. In this way 1.5 g of the title compound was obtained as a crystalline substance. Yield: 69.4
%. Melting point 100-104 [deg.] C.

Starting material 1- (2,6-diamino-4-)
Pyrimidinyl) piperazine-bis-trifluoroacetate was prepared by Step C of Example 60 and by deprotecting 1- (tertiary butoxycarbonyl) -4- (2,6-diamino-4-pyrimidinyl) piperazine. . The latter compound was prepared as described in step (a) of Example 59. Melting point of the obtained bis-trifluoroacetate: 192-198 ° C. Yield: 98.7
%.

The analogous 1- (2,6-diamino-4-pyrimidinyl) homopiperazine is prepared according to the procedure of Example 19 in 2,6-diamino-
Prepared by reacting 4-chloropyrimidine with unprotected homopiperazine (5 molar equivalents). Yield of base obtained: 91.3%. Melting point 62-72 [deg.] C.

Examples 4-8 The procedure of Example 3 was carried out by using the appropriate starting materials to prepare the compounds of formula (I) shown in Table 7.
In Table 7, each of A ¹ and A ² represents a single bond, Lip and n are as shown in the table and Het is of the general formula (a) where R ¹ is shown in the table. The same as the above].

[0085]

[Table 7]

Example 9 1-Trityl-4- (2.6-diamino-4-pyrimidinyl) piperazine 1- (2.6-Diamino-4-pyrimidinyl) -piperazine-bis-trifluoro in acetonitrile (50 ml) A mixture of acetate (2.1 g, 5.1 mmol), potassium carbonate (1.0 g, 7.5 mmol) and trityl chloride (1.36 g, 5.0 mmol) is vigorously stirred at room temperature. After 3 hours, the solvent is evaporated under reduced pressure and the solid residue is stirred with 100 ml of water at room temperature for 1 hour. The yellow powdery substance is collected, washed with water and then dried. The crude product was purified by column chromatography on silica gel using a 9: 1 mixture of methylene chloride and methanol as eluent to give 0.88 g of the title compound. Yield: 40.4%. Melting point 152-160 [deg.] C.

Examples 10-14 The procedure of Example 9 was carried out by using the appropriate starting compounds to prepare the compounds of formula (I) shown in Table 8. In Table 8, each of A ¹ and A ² represents a single bond, Lip and n are as shown in the table and Het is of the general formula (a) [wherein R ¹ is as shown in the table. A group] is shown.

[0088]

[Table 8]

Examples 15-17 The procedure of Example 9 was carried out by using the appropriate starting compound to prepare the compounds of formula (I) shown in Table 9. In Table 9, each of A ¹ and A ² represents a single bond and Lip, Het and n are as shown in the table.

[0090]

[Table 9]

Example 18 1- (1-adamantyl) -4- (4-chloro-3-oxo-2,3-dihydro-5-pyridazinyl) -piperazine 1- (1-adamantyl) in ethanol (25 ml) Piperazine (2.2 g, 10 mmol), triethylamine (1.36 ml, 10 mmol) and 4.5-dichloro-3-oxo-2.3-dihydropyridazine (1.65).
g, 10 mmol) is heated under reflux for 5 hours. After cooling, the precipitated solid was collected, washed with ethanol and then dried to give 2.57 g of the title compound. Yield: 73.
6%. Melting point 292-294 [deg.] C. The above product is dissolved in a hot mixture of ethanol (25 ml), water (6 ml) and concentrated HCl (2 ml) and the solution is treated with decolorizing charcoal. After filtration, the hydrochloride salt of the title compound was isolated as colorless crystals by cooling. Yield: 2.0 g. Melting point 306-308
° C.

Example 19 1- (1-adamantyl) -4- (2,6-diamino-
4-Pyrimidinyl) -piperazine 2,6-diamino-4-chloropyrimidine (0.43 g, 3.0 mmol) and 1- in ethanol (30 ml).
(1-adamantyl) -piperazine (0.66 g, 3.0
(Mmol) is heated in a closed tube at 170 ° C. for 3 hours. After cooling, the solvent was removed and the solid residue was washed with water (45
ml) and acidified with concentrated HCl to pH = 3. The resulting mixture is heated to 50 ° C., insoluble material is filtered off and the clear solution is stirred and cooled with 10 N.
Alkaline with NaOH. Collect the precipitated crystals,
Wash with water until neutral and then dry. using this method,
0.79 g of the title compound is obtained in the form of its monohydrate.
Yield: 76.6%. Melting point 265-268 [deg.] C.

Example 20 1- [2-hydroxy-3- (1-naphthyloxy)-
Propyl] -4- (2,6-diamino-4-pyrimidinyl) piperazine 1- (2,6-diamino-4 in ethanol (60 ml)
A mixture of -pyrimidinyl) piperazine-bis-trifluoroacetate (0.85 g, 2.0 mmol) and potassium carbonate (0.69 g, 5.0 mmol) is stirred under reflux for 30 minutes. The mixture was filtered hot and the filtrate was filtered with 1,2-epoxy-3- (1-
A solution of naphthyloxy) -propane (0.6 g, 3.0 mmol) is added. The mixture is heated under reflux for 3 hours, the solvent is evaporated and the residue is taken up in ethyl acetate (80 m).
Partition between l) and water (80 ml). The aqueous layer is separated and extracted with ethyl acetate (40 ml). The combined organic extracts were washed once with brine, dried over MgSO ₄ and concentrated to the next. The residue, ethyl acetate as eluent, methanol and conc. NH ₄ OH 75: 20: to silica gel column chromatography using 5 mixture. In this way 0.58 g of the title compound is obtained as a foam. Yield: 74.3%. Melting point after grinding with isopropyl ether: 122-124 ° C. L
Starting epoxides of formula (IV) in which ip represents 1-naphthyloxy are known methods [E. Fourneau, M. Trefouel, Bull.
Soc. Chim. France [4], 43 , 454 (1928)].

Examples 21-30 Example 20 by using the appropriate starting compound
Was carried out to produce the compound of formula (I) shown in Table 10. In Table 10, A ¹ is 2-hydroxy-1,3
Represents propylene, A ² represents a single bond, Lip and n are as shown in the table and Het is of the general formula
(a) [in the formula, R ¹ is as shown in the table].

[0095]

[Table 10]

1,2-epoxy-2- (naphthyloxy) used as the starting compound in Examples 24 to 30
-Propane (melting point 51-56 ° C, yield: 52.7%) and 1,2-epoxy-3- (1-oxo-1,2,3,4).
-Tetrahydro-6-naphthyloxy) propane (oil,
Yield: 87.9%) is obtained from E. Fourneau and M. Tr mentioned above.
Produced by the method of efouel.

Example 31 1- [2- (1-naphthyloxy) acetyl] -4-
(2,6-Diamino-4-pyrimidinyl) -piperazine 1- (2,6-diamino-4-pyrimidinyl) piperazine-bis-trifluoroacetate (1.1 g, 2.5 mmol) in acetonitrile (100 ml) and A suspension of potassium carbonate (1.38 g, 10 mmol) is stirred vigorously under reflux for 30 minutes. Then a solution of 2- (1-naphthyloxy) acetyl chloride (0.65 g, 3.0 mmol) in acetonitrile (5 ml) is added dropwise and the mixture is heated under reflux for 1 hour. Then the insoluble matter is filtered off hot and the filtrate is concentrated. Residue in water 1
Stir for 1 hour with 00 ml, collect the precipitate formed, wash with water until neutral and then dry to give the title compound 0.9.
0 g was obtained. Yield: 59.2%. Melting point 205-210
° C.

Example 32 1- [2- (2-naphthyloxy) acetyl] -4-
[2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl] homopiperazine To a solution of 2- (2-naphthyloxy) acetic acid (1.1 g, 5.0 mmol) in anhydrous tetrahydrofuran (25 ml) was added carbonyl. -Diimidazole (0.80 g, 5.0 mmol) is added in small portions at room temperature with stirring. After 15 minutes 1- in anhydrous tetrahydrofuran (15 ml)
A solution of [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] homopiperazine (1.58 g, 5.0 mmol) is added dropwise. The mixture is stirred at room temperature for 8 hours and the solvent is distilled off under reduced pressure. The residue is dissolved in methylene chloride, the solution is washed 3 times with water, dried over MgSO ₄ and then concentrated. The crude product obtained was chromatographed on a silica gel column using a 1: 2 mixture of benzene and ethyl acetate as the developing solvent to give 0.7 g of the title compound. Yield: 28%. Melting point 103-110
° C.

Example 33 1- [2- (1-naphthyloxy) acetyl] -4-
[2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine Sodium metal (0.069 g, 3 mg-atom) was dissolved in absolute ethanol (4 ml) and the resulting solution was added to ethanol (30 ml). ) 1-naphthol (0.3)
6 g, 2.2 mmol) and 1- (2-chloroacetyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine (0.9 g, 2.4 mmol). . The reaction mixture is heated under reflux for 4 hours, cooled to room temperature and the insolubles are filtered off. The filtrate is concentrated to dryness and the residue is chromatographed on a silica gel column using a 1: 2 mixture of benzene and ethyl acetate as the developing solvent. The product obtained was triturated with isopropyl ether to give 0.75 g of the title compound. Yield: 72.0%. Melting point 156-160 [deg.] C.

Starting 1- (2-chloroacetyl) -4-
[2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine was produced as follows. 1-
[2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine (1.65 g, 5.4 mmol) was dissolved in anhydrous chloroform (30 ml) and the dissolution was adjusted to 0-5.
Cooled to 0 ° C. and 2-chloroacetyl chloride (0.50 ml, 0.79 g, 7.0 mmol) in anhydrous chloroform (5 ml) is added dropwise with stirring. The mixture is stirred for 1 hour, concentrated and the residue is dissolved in 100 ml of water.
The aqueous solution is made alkaline with concentrated NH ₄ OH and stirred for 1 hour. During this time, the separated oil solidifies. The solid is collected, washed with ice cold water until neutral and then dried. In this way 2.0 g of the desired chloroacetyl compound was obtained. Yield: 97.0%. Melting point 153-156
° C. 1- (2-chloroacetyl) -4- [2,6-di (1-pyrrolidinyl) -4-pyrimidinyl] -homopiperazine was prepared in a similar manner and obtained as a tan viscous oil. Yield: 98.2%.

Examples 34-36 The procedures of Examples 31 or 32 were carried out by using the appropriate starting compounds to prepare the compounds of formula (I) shown in Table 11. In Table 11, A ¹ represents CH ₂ CO, A ² represents a single bond, Lip and n are as shown in the table, and Het is represented by the general formula (a) [wherein R is ¹ is as shown in the table].

[0102]

[Table 11]

Example 37 6- [4- [3- [4- (1-adamantyl) -1-piperazinyl] -2-hydroxypropoxy] phenyl]
-2,4,7-triaminopteridine 4- [3- [4- (1-adamantyl) -1-piperazinyl] -2-hydroxypropoxy] benzyl cyanide (3.44 g, 8.4 mmol), 5- Nitroso-2,
A mixture of 4,6-triamino-pyrimidine (1.08 g, 7.0 mmol) and 0.2 N sodium- (2-ethoxyethoxide) (35 ml) in 2-ethoxyethanol was stirred at 120 ° C. for 30 minutes. . After cooling to about 90 ° C. 100 ml of water are added and the mixture is cooled to room temperature and then stirred for 30 minutes in an ice-water bath. The precipitate was collected, washed with water and acetonitrile to give the title compound (3.23g)
Was obtained as a yellow powder. Melting point 287-289 [deg.] C (decomposition). Yield: 84.6%. 0.27 g of the above product (0.5
Mmol) in water (1 ml) to L (+)-tartaric acid (0.2
3 g, 1.5 mmol) dissolved in a hot solution and the resulting solution is cooled. Precipitated crystals were collected, washed with acetonitrile and dried to give the title compound ditertarate pentahydrate. Melting point 165-175 [deg.] C. Yield of salt formation:
38.3%.

Departure 4- [3- [4- (1-adamantyl)
-1-Piperazinyl] propoxy] benzyl cyanide was prepared as follows. 1- (1-adamantyl) piperazine (4.4 g, 2) in methanol (45 ml)
0 mmol) and 4- (2,3-epoxypropoxy) benzyl cyanide (2.9 g, 15.4 mmol).
The solution of is stirred at room temperature for 4 hours. Then the solvent is removed under reduced pressure and the residue is dissolved in ethyl acetate.
The solution was washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The residue was triturated to give 3.67 g of the desired substituted benzyl cyanide as pale yellow crystals. Yield: 45.8%. Melting point 136-138 [deg.] C.

Example 38 6- [4- [2-hydroxy-3- [4- (tertiarybutoxycarbonyl) -1-piperazinyl] propoxy] phenyl] -2,4,7-triaminopteridine Sodium metal (0 0.22 g, 9.6 mg-atom) 40 to
Dissolve in 2-ethoxyethanol (60 ml) at 50 ° C,
The solution was cooled to room temperature and 5-nitroso-2,4,6
-Triamino-pyrimidine (1.46 g, 9.5 mmol) was added, followed by 4- [2-hydroxy-3- [4- (tertiary butoxycarbonyl) -1 prepared as described in Example 45. -Piperazinyl] propoxy] benzyl cyanide (3.92 g, 10.4 mmol) is added. The mixture is stirred under nitrogen atmosphere for 1 hour under reflux and the dark brown solution obtained is diluted with 200 ml of ethyl acetate which is cooled to room temperature, after which the precipitate is collected, washed with ethyl acetate and dried. A yellow powder was obtained. Melting point 244-246 [deg.] C (decomposition). The filtrate is concentrated and the residue is dissolved in 30 ml of methanol. After treatment with decolorizing charcoal, the solution is concentrated to a volume of 10 ml and the crystals which have precipitated are collected. Overall yield of two formations: 84.8%.

Examples 39-44 Example 38 was prepared by using the appropriate starting compound.
Was carried out to produce the compound of formula (I) shown in Table 12. In Table 12, Lip is o-chlorotrityl (o-Cl-Tr) or tertiary butoxycarbonyl (B
oc), A ¹ represents a single bond, and n and A ² are
As shown in the table and Het has the general formula (g)
[In the formula, X is as shown in the table].

[0107]

[Table 12]

The compounds of formula (VIII) used as starting materials in Examples 39-44 are prepared according to the following Examples 45-
Prepared as described in 49. Example 45 4- [2-Hydroxy-3- [4- (tertiary butoxycarbonyl) -1-piperazinyl] propoxy] -benzyl cyanide 4- (2,3-epoxypropoxy) benzyl cyana in methanol (35 ml) A solution of the id (2.84 g, 15 mmol) and 1- (tertiary butoxycarbonyl) piperazine (4.2 g, 22.5 mmol) was stirred at room temperature for 3 hours and then the solvent was removed. The residue is converted to ethyl acetate 20
Dissolve in 0 ml, wash with water, dry over MgSO ₄ and concentrate. The crude product obtained is chromatographed on a silica gel column using ethyl acetate as eluent. The sticky substance obtained was triturated with hexane to give 3.95 g of the title compound. Yield: 70.2
%. Melting point 98-100 [deg.] C. Similarly, 4- [2-hydroxy-3- [4- (tertiary butoxycarbonyl) -1-
Homopiperazinyl] propoxy] benzyl cyanide was prepared. It was obtained as an oil in a yield of 69.9%. [Using 1- (tertiary butoxycarbonyl) homopiperazine obtained as an oil in a yield of 38.8% by the procedure described for the related piperazine derivatives in published German patent application 2,550,111. Depart].
4- [2-Hydroxy-3- [4- (o-chlorotrityl) -1-piperazinyl] propoxy] benzylcyanide was also prepared in a similar manner. Yield: 63.8
%. Melting point 103-106 [deg.] C. [The starting material for the preparation of this latter compound, namely 1- (o-chlorotrityl) -piperazine, was prepared by first adding 1-formylpiperazine to 1 molar equivalent of acetonitrile in the presence of 1 molar equivalent of potassium carbonate. Alkylation with trityl chloride (3 hours at room temperature) and the resulting 1-formyl-4-
(O-chlorotrityl) piperazine (melting point 245-24
7 ° C. Yield: 89.5%) in butanol with an equal weight of N 2.
Prepared from 1-formylpiperazine by deformylating by refluxing with aOH. Yield: 82.0%. Melting point 178-180 [deg.] C.

Example 46 4- [2-Hydroxy-3- [4- (tertiary butoxycarbonyl) -1-piperazinyl] propylamino] benzylcyanide Step (a) 4- (2,3-epoxypropyl-amino) ) Benzyl cyanide A mixture of 4-aminobenzyl cyanide (10 g, 75.7 mmol), epichlorohydrin (7.9 ml, 9.25 g, 100 mmol), ethanol (15 ml) and water (10 ml) was refluxed. 2 below
Heat for hours. After cooling, the reaction mixture is poured onto 100 ml of water and extracted with ether (3 x 50 ml). Combine the organic extracts and 50 ml of 10N NaOH for 3 hours at room temperature.
Stir with. The organic layer was separated, washed neutral with water, dried over MgSO ₄ and concentrated to the next. The residue was mixed with benzene and ethyl acetate 3: 1 as a developing solvent.
Chromatography on a silica gel column using the mixture gave 7.24 g of the title compound as an oil. Yield: 51.0%.

Step (b) 4- [2-Hydroxy-3- [4- (tertiary butoxycarbonyl) -1-piperazinyl] propylamino] benzylcyanide Described in step (a) above in methanol (30 ml). A solution of the epoxide thus obtained (4.96 g, 26.4 mmol) and 1- (tertiary butoxycarbonyl) piperazine (6.4 g, 34.4 mmol) was added under reflux to 2
Heat for hours and isolate the product as described in Example 45. The crude product obtained was chromatographed on a silica gel column using a 9: 1 mixture of ethyl acetate and methanol as the developing solvent to give the title compound (3.68 g). Melting point 86-87 [deg.] C. Yield: 37.2%.

Example 47 4- [N-methyl-N- [2-hydroxy-3- [4-
(3rd butoxycarbonyl) -1-piperazinyl] propyl] amino] benzyl cyanide Step (a) 4- [N-methyl-N- (2,3-epoxypropyl)
Amino] benzyl cyanide 4-methylaminobenzyl cyanide (3.05 g, 2
0.9 mmol), epichlorohydrin (2.4 ml, 2.
A mixture of 87 g, 31 mmol), ethanol (25 ml) and water (20 ml) is heated under reflux for 3 hours. After cooling, the mixture was diluted with ethanol (10 ml) and aqueous 10N NaOH (6 ml) was added. The clear solution obtained is stirred at room temperature for 1 hour and the ethanol is distilled off. The residue was diluted with 100 ml of water and ether (3 x
Extract with 50 ml). The organic extract was washed neutral with brine, dried over MgSO _4, and then concentrated. The residue is chromatographed on a silica gel column using a 3: 1 mixture of benzene and ethyl acetate as the developing solvent to give the title compound 2.21 as an oil.
g was obtained. Yield: 52.2%.

Step (b) 4- [N-methyl-N- [2-hydroxy-3- [4-
(3rd butoxycarbonyl) -1-piperazinyl] propyl] amino] benzyl cyanide The epoxide (2.21 g, 10.9 mmol) prepared as described in step (a) above was treated with the procedure of Example 46 ( By operation b), it is reacted with 1- (tertiary butoxycarbonyl) piperazinyl (3.05 g, 16.4 mmol) and the product is isolated as described in example 46 step (b). In this way 4.02 g of the title compound was obtained as an oil. Yield: 94.8%.

Example 48 4- [2-Hydroxy-3- [4- (tertiary butoxycarbonyl) -1-piperazinyl] propylthio] benzyl cyanide Step (a) 4- (N, N-dimethylthiocarbamoyloxy) Benzyl cyanide Sodium metal (1.15 g, 50 mg-atom) is dissolved in methanol (100 ml) and 4-hydroxybenzyl cyanide (6.7 g, 50 mmol) is added.
The resulting solution was concentrated and acetonitrile (2x
10 ml) is evaporated from the residue. The salt obtained is dissolved in anhydrous dimethylformamide (200 ml) and about 25 ml of solvent are removed under reduced pressure. In the resulting solution,
N, N-dimethylthiocarbamoyl chloride (9.9
g, 80 mmol) and the reaction mixture at 80-8.
Stir at 5 ° C. for 2 hours. Thereafter, additional N, N-dimethylthiocarbamoyl chloride (2.5 g, 20 mmol) is added and stirring is continued for another hour at 80 ° C. After cooling, the mixture is poured into aqueous 1% KOH (500 ml) and extracted with ether (3 x 200 ml). The organic extract was washed with water until neutral, dried over MgSO ₄ and concentrated to the next. The solid residue was triturated with water and after drying triturated with isopropyl ether to give the title compound (5.42g). Melting point 120-1
24 ° C. Yield: 52.7%.

Step (b) 4- (N, N-Dimethylcarbamoylthio) benzyl cyanide Dowsum A (75 ml) preheated to 250 ° C. under nitrogen.
Is added to the compound prepared as described in step (a) above (5.05 g, 22.9 mmol) and the mixture is stirred at the same temperature for 1 hour. After cooling, the reaction mixture is diluted with 200 ml of benzene, treated with decolorizing charcoal and then the solvent is distilled off under reduced pressure. The residue was chromatographed on a silica gel column using a 3: 1 mixture of benzene and ethyl acetate as the developing solvent to give the title compound as yellow crystals (3.08 g). Yield: 60.1
%. Melting point 97-99 [deg.] C.

Step (c) 1- (2,3-epoxypropyl) -4- (tertiary butoxycarbonyl) piperazine 1- (tertiary butoxycarbonyl) piperazine (18.6 g, 100 mmol) in methanol (50 ml). And a solution of epichlorohydrin (10.2 ml, 12.0 g, 130 mmol) is stirred at room temperature for 24 hours and then the solvent is evaporated. The residue is dissolved in 200 ml of ether and the solution is stirred with 10N aqueous NaOH (100 ml) for 2 hours at room temperature. The organic layer was then separated, washed with brine until neutral, dried over MgSO ₄ and concentrated to give the title compound as a pale yellow viscous oil (21.
8 g) was obtained. Yield: 90.1%. Step (d) 4- [2-hydroxy-3- [4- (tertiary butoxycarbonyl) -1-piperazinyl] propylthio] benzyl cyanide The product of step (b) above (3.08 g, 14 mmol), above. Epoxide (3.4 g, 14 mmol) prepared as described in step (c), ethanol (7
A mixture of 0 ml) and 2N aqueous NaOH (7 ml) is heated at reflux under a nitrogen atmosphere for 2 hours. After cooling, the mixture is poured into 300 ml of water and ethyl acetate (2 x 15
0 ml). The organic layer was washed neutral with brine, dried over MgSO ₄ and concentrated to the next. The residue,
Chromatography on a silica gel column using ethyl acetate as the developing solvent gave 1.69 g of the title compound as a colorless solid. Yield: 30.8%. Melting point after trituration with hexane: 69-70 ° C.

Example 49 4- [2- [4- (tertiary butoxycarbonyl) -1-piperazinyl] acetylamino] benzylcyanide Step (a) 4- (2-chloroacetylamido) benzylcyanide 2-chloro Acetyl chloride (3.3 ml, 5.0 g, 4
4 mmol) at 10-15 ° C in 4-aminobenzylcyanide (5.
3 g, 40 mmol) and the mixture is stirred at room temperature for 1 hour. After pouring into water, the precipitate was collected, washed with water and then dried under reduced pressure over P ₂ O ₅ to give the title compound (7.33 g) as almost colorless crystals.
Yield: 87.8%. Melting point 124-125 [deg.] C. Step (b) 4- [2- [4- (tertiary butoxycarbonyl) -1-piperazinyl] acetylamino] benzylcyanide The product obtained by step (a) above in acetonitrile (50 ml) (2.1 g A mixture of 10 mmol) 1- (tertiary butoxycarbonyl) piperazine (2.4 g, 13 mmol) and potassium carbonate (1.8 g, 13 mmol) is stirred under reflux for 12 hours. After cooling, the mixture is poured into water. The precipitate is collected, washed with water and then under reduced pressure P
Drying over ₂ O ₅ gave 3.48 g of the title compound as almost colorless crystals. Yield: 97.2%. Melting point 137-13
8 ° C.

Example 50 6- [4- [2-Hydroxy-3- (1-piperazinyl) propoxy] phenyl] -2,4,7-triaminopteridine Method (A) protected by Example 38. Compound (5.5
g, 10.8 mmol) and 10% aqueous HCl (14
0 ml) of the mixture is stirred at room temperature for 20 hours. The yellow suspension is diluted with 350 ml of water and heated to about 40 ° C. The solution obtained is filtered and made alkaline with 5N aqueous NaOH. The precipitate that formed was collected, washed with water until neutral and then dried to give the title compound (4.4 g) as pale yellow crystals. Yield: 100%. Melting point 245-2
55 ° C. 3.91 g (9.5 mmol) of the above product are added to a solution of L (+)-tartaric acid (3.54 g, 23.6 mmol) in water (60 ml) and the solid is dissolved by heating to reflux. . The hot solution is treated with decolorizing charcoal, filtered and cooled. The precipitated crystals were collected, washed with water and acetonitrile and then dried to obtain the title compound ditertarate-trihydrate. Melting point 185-190 [deg.] C. Yield of salt formation: 66.9%.

Method (B) Protected compound obtained according to Example 38 in a 1.5N solution of HCl in ethyl acetate (20 ml) (1.5 g,
3 mmol) suspension is stirred at room temperature for 5 hours. The solid (HCl salt of the title product) is then collected and then dried and dissolved in water. The solution is made alkaline with aqueous 5N NaOH and the precipitated base is filtered off to give the title compound which is identical to the product obtained by method (A) above. Yield: 37.0%. Method (C) Protected compound obtained according to Example 38 (0.26 g, 0.5 mmol) and L (+) in water (2.5 ml).
A mixture of tartaric acid (0.23 g, 1.5 mmol) is heated under reflux for 1 hour and cooled to room temperature. The deposited precipitates were collected to obtain the title compound, ditertarate-trihydrate, which is the same as the salt obtained by the method (A). Yield: 6
5.8%. Melting point 169-175 [deg.] C.

Examples 51-55 The procedure of Example 50 was carried out by using the appropriate starting compounds prepared according to Examples 40-44 to prepare compounds of formula (I) shown in Table 13. In Table 13, Lip is hydrogen, A ¹ represents a single bond,
n and A ² are as shown in the table and Het
Is the general formula (g) (wherein X is as shown in the table)
The group of is shown.

[0120]

[Table 13]

Example 56 6- [4- [3- (1- (1-piperazinyl) propylamino] phenyl] -2,4,7-triaminopteridine 4- [3- (4-formyl-1-piperazinyl) propylamino ] Benzyl cyanide (1.15 g, 4.0 mmol), 5-nitroso-2,4,6-triamino-pyrimidine (0.56 g, 3.6 mmol) and 0.2 N + sodium in 2-ethoxyethanol- A mixture of (2-ethoxy-ethoxide) (18 ml) is stirred under reflux for 3 hours, then NaOH (0.14 g, 3.5 mmol) is added and stirring under reflux is continued for a further 2.5 hours. After cooling, the mixture is diluted with 100 ml of ether. The precipitated precipitate was collected, washed with ether then water and dried to give the title compound (0.9 as a yellow powder).
2 g) was obtained. Yield: 64.8%. The above product is treated with water (6 m
After dissolving in a hot solution of L (+)-tartaric acid (0.75 g, 5 mmol) in 1) and cooling, the mixture was added to methanol (6
ml) to dilute. The precipitated crystals were collected, washed with methanol and then dried to obtain the title compound ditertarate.
Melting point 170-178 [deg.] C. Yield of salt formation: 51.9%.

The starting 4- [3- (4-formyl-1-piperazinyl) propylamino] benzyl cyanide was prepared as follows. Step (a) 1-formyl-4- (3-chloropropyl) piperazine 1-formylpiperazine (5.7 g, 50 mmol),
1-Bromo-3-chloropropane (7.2 ml, 11.8
A mixture of g, 75 mmol) and chlorobenzene (30 ml) is stirred at 100-105 ° C for 3 hours. After cooling, the precipitated 1-formylpiperazine hydrochloride (4.58)
g, yield: 94.4%) is filtered off and the filtrate is concentrated. The residue was chromatographed on a silica gel column using an 8: 2 mixture of ethyl acetate and methanol as a developing solvent to give the title compound as an oil, 2.46.
g was obtained. Yield: 51.6%. Step (b) 4- [3- (4-formyl-1-piperazinyl) propylamino] benzyl cyanide 1-formyl-4- (3) prepared by the above step (a)
-Chloropropyl) piperazine (1.0 g, 5.2 mmol), 4-aminobenzyl cyanide (0.66 g, 5
And a sodium iodide (0.15 g, 1 mmol) mixture is heated at 100-105 ° C. for 2 hours. After cooling, the mixture is dissolved in 40 ml of water and treated with decolorizing charcoal. The filtered solution is made alkaline with 2N aqueous NaOH and extracted with chloroform (3 x 20 ml). The organic extract was washed with water, dried over MgSO ₄ and concentrated to the next. The residue was chromatographed on a silica gel column using a 2: 1 mixture of ethyl acetate and methanol as the developing solvent to give the title compound. 0.55 g (38.5%). Melting point after trituration with ether: 85-87 ° C.

Example 57 1- (1-adamantyl) -4- (4,7-diamino-)
6-phenyl-2-pteridinyl) piperazine Step (a) 1- (1-adamantyl) -4-amidinopiperazine hydroiodide The title compound is published European Patent Application No. 39,1.
Prepared as described for 1-formylpiperazine in 90 Example 1 starting from 1- (1-adamantyl) piperazine and S-methyl-isothiourea hydroiodide. Melting point 278-280 [deg.] C. yield:
72.3%. Step (b) 1- (1-adamantyl) -4-amidinopiperazine, isonitron malonitrile salt Sodium nitrite (0.74 g, 10.5 g) in water (1 ml).
A solution of malonitrile (0.6 mmol) at 0-5 ° C.
6 g, 10 mmol), water (1.2 ml) and acetic acid (0.1 ml).
7 ml) and the mixture is stirred first at the same temperature for 2 hours and then at ambient temperature for a further 3 hours. Thereafter, the reaction mixture is heated to 50 ° C. and then 2
A mixture of hydroiodide salt (3.12 g, 80 mmol) prepared by step (a) above in methanol (6 ml) made alkaline with N ethanolic NaOEt solution is added. The mixture obtained is stirred for 2 hours at 80 to 85 ° C., the insolubles are filtered off hot and the filtrate is concentrated. Triturate the residue with water to give the crude title product 2.40.
g was obtained. Yield: 83.9%. The crude product is dissolved in acetone, the insolubles are filtered off and the filtrate is concentrated to dryness to give the title compound in pure form. Melting point 182-
186 ° C.

Step (c) 1- (1-adamantyl) -4- (4,7-diamino-)
6-Phenyl-2-pteridinyl) piperazine 2-ethoxyethanol (7 ml) in a solution of the salt (0.50 g, 1.4 mmol) prepared as described in step (b) above, potassium carbonate (0 0.13 g, 0.9 mmol) is added and the mixture is heated under reflux for 90 minutes.
After cooling to about 60 ° C., NaOH (0.08 g, 2 mmol) was added, followed by 2-ethoxyethanol (2 ml).
Benzyl cyanide (0.25 ml, 2.2 mmol) in it is added dropwise at the same temperature. The mixture is stirred at 80 ° C. for 2 hours, cooled and then diluted with 50 ml of water. The resulting precipitates are collected, washed with water and acetone to give the title compound (0.37
g) was obtained. Yield: 57.8%. Melting point 293-297 ° C
(Disassembly). Using anhydrous HCl in ethyl acetate,
The product was converted to its hydrochloride salt. Melting point> 231 ° C
(Disassembly).

Example 58 1- (4,7-Diamino-6-phenyl-2-pteridinyl) piperazine Step (a) 1- (3rd butoxycarbonyl) -4-amidinopiperazine hydroiodide The title compound is Published European Patent Application No. 39,1
Prepared as described for 1-formylpiperazine in Example 1 of 90, starting from 1- (1-tert-butoxycarbonyl) piperazine and S-methyl-isothiourea hydroiodide. Melting point 180-182
° C. Yield: 66.3%. Step (b) 1- (tertiary butoxycarbonyl) -4-amidinopiperazine The title compound was prepared according to the procedure described in step (b) of Example 57 according to the procedure described in step (b) above. Manufactured starting from. Yield: 85.5%.
Melting point 155-162 [deg.] C.

Step (c) 1- (3rd Butoxycarbonyl) -4- (4,7-diamino-6-phenyl-2-pteridinyl) piperazine The title compound was prepared according to the procedure described in Example 57, step (c). Was prepared starting from the salt obtained by step (b) above. Yield: 40%. Melting point 240-2
42 ° C. Step (d) 1- (4,7-diamino-6-phenyl-2-pteridinyl) piperazine Protected compound prepared by step (c) above (3.8 g, 9 mmol) and 97% formic acid (20 ml).
The mixture is stirred at room temperature for 5 hours. Then the mixture is poured into 200 ml of water and the pH is adjusted to 10 with 10N NaOH. The precipitated solid was collected, dried and recrystallized from acetonitrile to give the title compound (1.63g). Yield: 56.2%. Melting point 244-247 [deg.] C. The above product was converted to its hydrochloride salt using anhydrous HCl in ethyl acetate.

Example 59 1- (2,7-Diamino-6-phenyl-4-pteridinyl) piperazine Step (a) 1- (3rd butoxycarbonyl) -4- (2,6-diamino-4-pyrimidinyl) Piperazine 2,6-diamino-4-in chlorobenzene (30 ml)
Chloropyrimidine (2.88 g, 20 mmol) and 1- (tertiary butoxycarbonyl) piperazine (5.6 g,
30 mmol) is stirred under reflux for 3 hours.
After cooling, the precipitate formed was collected and aqueous 1N NaOH.
Stir with (63 ml) at room temperature for 15 minutes. The solid is collected, washed with water and dried. Yield: 90.4%.
Melting point 176-179 [deg.] C. Step (b) 1- (3rd butoxycarbonyl) -4- (2,6-diamino-5-nitroso-4-pyrimidinyl) piperazine Sodium nitrite (4.24 g, 64.64) in water (43 ml).
A solution of 6 mmol) is added dropwise at 10 ° C. to a mixture of the product obtained from step (a) above (18.1 g, 64.6 mmol) and acetic acid (180 ml). 1 of this mixture
Stir for hours and collect the precipitate. The product is stirred with a 10% aqueous solution of potassium carbonate (230 ml) at room temperature for 1 hour. The pink solid formed is collected, washed with water and dried at 100 ° C. Yield: 94.8%. Melting point 235-240 ° C (decomposition).

Step (c) 1- (tertiary butoxycarbonyl) -4- (2,7-diamino-6-phenyl-4-pteridinyl) piperazine The title compound was prepared in place of sodium- (2-ethoxyethoxide). Prepared according to the procedure of Example 37 except that NaOH was used as the base, by reacting the product obtained as described in step (b) above with benzyl cyanide. Melting point 245-246 [deg.] C. Yield: 54.7%. Step (d) 1- (2,7-diamino-6-phenyl-4-pteridinyl) piperazine According to the method (B) of Example 50, the above step (c) is performed.
Deprotection of the compound obtained by to give the title compound in 83.0% yield. Melting point (base) 265-
275 ° C. The above product was converted to its ditartrate salt according to the method (A) of Example 50. Melting point 15
0-155 ° C.

Example 60 1- (2,4,7-triamino-6-pteridinylcarbonyl) piperazine Step (a) 1- (3rd butoxycarbonyl) -4- (2-cyanoacetyl) piperazine 1- ( Third butoxycarbonyl) piperazine (37.2
5 g, 0.20 mol) and ethyl cyanoacetate (22.6
g, 0.20 mol) at 150-155 ° C.
Heat for hours. After cooling, the mixture solidifies. Ground with isopropyl ether to give the title compound 24.7
g was obtained. Melting point 143-145 [deg.] C. Yield: 48.8%. Step (b) 1- (tertiary butoxycarbonyl) -4- (2,4,7-triamino-6-pteridinylcarbonyl) piperazine The title compound was prepared according to the procedure described in Example 37. ) Was prepared by reacting the compound obtained by) with 5-nitroso-2,4,6-triamino-pyrimidine. Yield: 59.1%. Melting point 245-2
50 ° C. Step (c) 1- (2,4,7-triamino-6-pteridinylcarbonyl) piperazine The protected compound obtained as described in step (b) was treated with a 2-fold (v / w) amount. 5 with trifluoroacetic acid
Stir at -10 ° C for 1 hour, dilute with 10 volumes (v / v) of methanol and collect the precipitate. In this way,
A bis-trifluoroacetate salt of the title compound was obtained.
Melting point 233-238 [deg.] C. Yield: 69.8%.

Formulation examples will be given below. The active ingredient, magnesium silicate and lactose are mixed and kneaded with an alcohol solution containing 5% hydroxypropylcellulose, then granulated to an appropriate particle size, dried and sized, and then magnesium stearate and plant. Hardened oil is added and mixed to make uniform granules. Then, a tablet having a diameter of 7.0 mm, a weight of 150 mg and a hardness of 6 kg was prepared with a rotary tableting machine.

[0131] After mixing the respective raw materials except hydroxypropyl cellulose in the above formulation example, an alcohol solution containing hydroxypropyl cellulose was added thereto and kneaded, then granulated by an extrusion granulator, and dried to obtain granules. . The granules were sized to obtain granules (12 to 48 mesh).

[0132] Sucrose, D-sorbitol, methyl paraoxybenzoate,
Propyl paraoxybenzoate and the above active ingredients are dissolved in 60 g of warm water. After cooling, a solution of flavoring agent dissolved in glycerin and ethanol is added. Then water is added to the mixture to bring it to 100 ml.

[0133] Sodium chloride and the active ingredient are dissolved by adding distilled water to make the total volume 1.0 ml.

[0134] Glycerin is added to the active ingredient and dissolved. Polyethylene glycol 4000 is added thereto, heated and dissolved, and then poured into a suppository and cooled and solidified to produce 1.5 g of a suppository.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication location A61K 31/505 ABG ABX 9360-4C ACF C07D 239/48 8615-4C 239/94 8615-4C 403 / 06 237 8829-4C 239 8829-4C (72) Inventor Ferenz Andrassi Budapest, Hungary 1125. Ktov Oergi Utsua 69 (72) Inventor Estel Hodoura Budapest, Hungary 1107. Bihariutu Tour 5 / Be (72) Inventor Rayos Toldeu, Budapest, Hungary 1118. Weitler Nii Tutua 53 (72) Inventor Clara Szyutka Budapest Hungary 1031. Vizmolnar Ututua 6 (72) Inventor Giuzanna Fitztrell Budapest, Hungary 1088. St. Kirari Iuttua 35 (72) Inventor Larslow Siebeshyu Tjane Budapest, Hungary 1157. Coeraca Caspar Park 44 (72) Inventor Catalin Gergenii Budapest 1026, Hungary. Gabor Ah Ututua 42 (72) Inventor Ishiyutvaan Siraki 1054. Budapest, Hungary. Bartoli Tutua 12 (72) Inventor Josef Zimesh 1137 Budapest, Hungary. Saint-Issh Jutvaan Parc 10 (72) Inventor Varea Leyte Vuitkotsui Budapest 1157, Hungary. Heve Ezier Utsutua 7

Claims (4)

[Claims] 1. A compound represented by the general formula (I): Compounds and salts of these compounds. In the above formula, Lip is hydrogen; C ₁₅ -C ₂₀ alkyl; C ₁₀ -C ₂₀ alkanoyl or C ₁₀ -C ₂₀ alkenoyl; optionally substituted by halogen as the case trityl; adamantyl; 1- or 2- Naphthyloxy or oxo substituted tetrahydronaphthyloxy; or represents an amine protecting group commonly used in peptide chemistry, wherein A ¹ and A ² are independently a single bond and optionally substituted by hydroxy or oxo Optionally selected from the group consisting of C ₂ -C ₃ alkylene, n is 1 or 2 and Het is of the general formula (a) (Wherein R ¹ is amino or 1-pyrrolidinyl)
Or a group of formula (b) 4-chloro-3-oxo-2,3-dihydro-5-pyridazinyl group of formula (c) 4-amino-6,7-dimethoxy-2-quinazolinyl group of formula (d) 4,7-diamino-6-phenyl-2-pteridinyl group of formula (e) 2,7-diamino-6-phenyl-4-pteridinyl group of formula (f) A 2,4,7-triamino-6-pteridinylcarbonyl group of, or a compound represented by the general formula (g): (Wherein X represents oxygen, sulfur or nitrogen optionally substituted by lower alkyl), with the proviso that, firstly, Het represents a group of general formula (a) If shown and A ¹ and A ² both mean a single bond, Lip is not hydrogen, and secondly, if Lip is different from naphthyloxy or oxo-substituted tetrahydronaphthyloxy, then A
¹ means a single bond; thirdly, when Lip represents naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ is not a single bond, and fourthly, A ¹ and A ² are At the same time, C _2- , optionally substituted by hydroxy or oxo
It cannot represent C ₃ alkylene. 2. 1- (10-undecenoyl) -4-
[2,6-Di (1-pyrrolidinyl) -4-pyrimidinyl] piperazine, 1- [2-hydroxy-3- (2-naphthyloxy) propyl] -4- [2,6-di (1-pyrrolidinyl)- 4-pyrimidinyl] homopiperazine, 6
-[4- [2-hydroxy-3- (1-piperazinyl)
Propoxy] phenyl] -2,4,7-triaminopteridine, 6- [4- [N-methyl-N- [2-hydroxy-3- (1-piperazinyl) propyl] amino] phenyl] -2,4, A compound selected from the group consisting of 7-triaminopteridine and salts thereof. 3. A compound of the general formula (I) (wherein Lip, A ¹ , A ² , Het and n are as defined in claim 1 as a pharmaceutical ingredient mixed with a carrier and / or an additive commonly used in formulation). To a disease or disorder directly or indirectly associated with the in vivo pathological peroxidation process, which comprises a novel compound (as defined) or a pharmaceutically acceptable acid addition salt thereof. A pharmaceutical composition for treating an affected patient, especially for the treatment or prevention of diseases and disorders in which prevention of lipid peroxidation is desired. 4. (a) General formula (I): Wherein Lip is as defined in claim 1, with the proviso that it is not a hydrogen or amine protecting group and A ¹ is, if Lip represents naphthyloxy or oxo substituted tetrahydronaphthyloxy, It is as defined in claim 1 and n, A ² and Het are as defined in claim 1 with the proviso that it is not a single bond], to prepare a compound of general formula (II ) Lip-A ¹ -L ¹ (II), wherein Lip and A ¹ are as described above and L ¹ is a scavenging group, and is represented by the general formula (III) (Where n, A ² and Het are as described above).
Or (b) a compound of the general formula (I) [wherein Lip represents naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ represents 1,3-propylene substituted by hydroxy, and n, A ² and Het are as defined in claim 1) to prepare a compound of general formula (IV) (Wherein Lip is as described above), a compound of the general formula (III) (Where n, A ² and Het are as described above).
Or (c) General Formula (I) [wherein Lip is as defined in claim 1 with the proviso that it is not hydrogen, and A ¹ is Lip is naphthyloxy. Or, with the proviso that A ¹ is not a single bond when it represents an oxo-substituted tetrahydronaphthyloxy and other conditions that A ¹ is a single bond when Lip represents an amine protecting group. As defined, and n, A ² and Het are as defined in claim 1) to prepare a compound of general formula (V) (In the formula, Lip, A ¹ and n are as described above)
A compound of the general formula (VI) L ² -A ² -Het (VI) where A ² and Het are as described above and L ²
Represents a removing group), or (d)
General formula (I) [Lip means naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ is as defined in claim 1 with the proviso that it is not a single bond and n, A ² and Het are
A compound of general formula (VII): Wherein A ¹ , n, A ² and Het are as described above and L ¹ represents a leaving group, and a compound of the general formula Lip
-H (wherein Lip is as described above), or (e) General formula (I) [wherein Lip
Is as defined in claim 1 with the proviso that it is not naphthyloxy or oxo substituted tetrahydronaphthyloxy, A ¹ is a single bond, He
t is a general formula (g) (In the formula, X is as defined in claim 1.)
And n and A ² are as defined in claim 1) to prepare a compound of general formula (VIII) Where Lip is as described above with the proviso that it is not hydrogen, naphthyloxy or oxo substituted tetrahydronaphthyloxy and n, X and A ²
Is a compound of formula (IX) Is reacted with 5-nitroso-2,4,6-triaminopyrimidine and if Lip represents an amine protecting group, this protecting group is removed from the compound thus obtained,
Or (f) general formula (I) [Lip is as defined in claim 1 with the proviso that it is not naphthyloxy or oxo-substituted tetrahydronaphthyloxy, and A ¹ and A ² are both single Is a bond and He
t is the formula (d) Embedded image and n is as defined in claim 1 to prepare a compound of formula (X) Where Lip is as described above and n is as described above, provided that it is not hydrogen, naphthyloxy or oxo substituted tetrahydronaphthyloxy), and If Lip represents an amine protecting group, this protecting group is removed from the product thus obtained, or (g) the general formula (I) [wherein Lip is a naphthyloxy or oxo substituted As defined in claim 1, with the proviso that it is not tetrahydronaphthyloxy,
A ¹ and A ² are both single bonds and Het is of the formula
(e) [Chemical Formula 20] Embedded image and n is as defined in claim 1 to prepare a compound of formula (XI) Where Lip is as described above and n is as described above, provided that it is not hydrogen, naphthyloxy or oxo substituted tetrahydronaphthyloxy), and If Lip represents an amine protecting group, this protecting group is removed from the resulting product, or (h) the general formula (I)
[Lip is as defined in claim 1, with the proviso that it is not naphthyloxy or oxo-substituted tetrahydronaphthyloxy, and A ¹ and A ² are
Both are single bonds and Het has the formula (f) Embedded image and n is as defined in claim 1 to prepare a compound of general formula (XII) Where Lip is as described above and n is as described above, provided that it is not hydrogen, naphthyloxy or oxo-substituted tetrahydronaphthyloxy, and a compound of formula (IX) 24] Was reacted with 5-nitroso-2,4,6-triaminopyrimidine and, if Lip represents an amine protecting group, this protecting group was removed from the product thus obtained,
And, if desired, a compound of the general formula (I) comprising converting a compound of the general formula (I) prepared by any of the above-mentioned methods (a) to (h) into an acid addition salt thereof: 25] Wherein, Lip is hydrogen; C ₁₅ -C ₂₀ alkyl; C ₁₀ -C ₂₀ alkanoyl or C ₁₀ -C ₂₀ alkenoyl; optionally substituted by halogen as the case trityl; adamantyl; 1- or 2- Naphthyloxy or oxo substituted tetrahydronaphthyloxy; or represents an amine protecting group commonly used eg in peptide chemistry, wherein A ¹ and A ² are independently substituted by a single bond and optionally hydroxy or oxo Optionally selected from the group consisting of C ₂ -C ₃ alkylene, n is 1 or 2 and Het is of the general formula (a) (Wherein R ¹ is amino or 1-pyrrolidinyl)
Or a group of formula (b) A 4-chloro-3-oxo-2,3-dihydro-5-pyridazinyl group of formula (c) 4-amino-6,7-dimethoxy-2-quinazolinyl group of formula (d) 4,7-diamino-6-phenyl-2-pteridinyl group of formula (e) 2,7-diamino-6-phenyl-4-pteridinyl group of formula (f) 2,4,7-triamino-6-pteridinylcarbonyl group of or a compound represented by the general formula (g): (Wherein X represents oxygen, sulfur or nitrogen optionally substituted by lower alkyl), with the proviso that, firstly, Het represents a group of general formula (a) If shown and A ¹ and A ² both mean a single bond, Lip is not hydrogen, and secondly, if Lip is different from naphthyloxy or oxo-substituted tetrahydronaphthyloxy, then A
¹ means a single bond; thirdly, when Lip represents naphthyloxy or oxo-substituted tetrahydronaphthyloxy, A ¹ is not a single bond, and fourthly, A ¹ and A ² are At the same time, C _2- , optionally substituted by hydroxy or oxo
C ₃ alkylene cannot be shown] and a process for preparing a pharmaceutically acceptable salt thereof.